This project involves electron spin resonance (esr) investigations of a series of spin labeled analogues of morphine to obtain information about the structure of the opiate receptor site. A series of new derivatives of morphine labeled with nitroxide free radicals are being synthesized. The labels are connected to the morphine skeleton at various positions with connecting chains of differing length. The labeled molecules are bound to opiate receptors from synaptic membranes and the esr spectra of the drug-receptor complex is determined. The esr spectra is a very sensitive measure of the motion of the labeled portion of the molecule. Through studies of changes in the motional correlation time as a function of the length of the chain connecting the label to the opiate one can determine the "depth" of the receptor site at a given position of the morphine skeleton. Studies with labeled molecules substituted at a number of positions on the morphine rings allows one to determine the overall geometry of the drug-receptor complex. Work with both opiate agonist and antagonist are being conducted to determine binding geometries and the mechanism of binding. This project should produce detailed information on the mechanism by which analgesic drugs interact with receptors in the central nervous system and aid in the design of new drugs.